The long range goal of the principal investigator is to examine mechanisms that control peripheral blood flow. This proposal examines the arterial chemoreflex (sympathoexcitatory), its modulation by the lung mechanoreflex (sympathoinhibitory) and peripheral vascular effects of hypoxemia in humans. Our hypotheses are that 1) During hypoxemia (with spontaneous breathing) sympathetic vasoconstrictor traffic and norepinephrine (NE) release from nerve terminals is increased, yet adrenergic vasoconstriction does not occur and forearm vascular resistance decreases. The rise in plasma NE is attenuated because NE clearance rises during hypoxemia. Using a tritiated NE infusion technique, we will explore the mechanism of increased NE clearance during hypoxemia. 2) The forearm vasodilation observed during hypoxemia is not due to sympathetic neural withdrawal but may be secondary to cholinergic vasodilation and/or local vasodilator mechanisms. In experiments with intra-arterial infusion of atropine (cholinergic blockade) and aminophylline (adenosine receptor blockade) we will explore the mechanism(s) of vasodilation induced by hypoxemia. 3) The sympathoinhibitory effect of ventilation is crucial in opposing sympathoexcitation evoked by hypoxemia. We will measure muscle sympathetic nerve activity (MSNA, peroneal microneurography) and forearm and skin blood flow (plethysmography, laser Doppler velocimetry) to examine the effects of altered breathing with/without simultaneous chemoreceptor stimulation. 4) Periodic breathing, such as seen in patients with obstructive sleep apnea, is accompanied by striking hemodynamic oscillations. Marked blood pressure elevations occur immediately after apnea and may in part be mediated by hypoxemia or absent lung mechanoreflex activity (apnea). To determine the role of the sympathetic nervous system in this response, we will measure MSNA during simulated apnea (voluntary breathholding), and apnea during sleep (spontaneous). Periodic (Cheyne-Stokes) breathing is also very common in heart failure, especially during sleep. If in heart failure, hemodynamic oscillations similar to sleep apnea occur, these intermittent increases in left ventricular afterload may further impair circulatory function. To determine whether these reflexes are important in heart failure, we will perform microneurography studies in these patients. These studies will be conducted in an active clinical research environment using a multidisciplinary approach. The findings will provide new insight into mechanisms of circulatory control and may have important implications in disease.